Neural Melanocortin Signaling and Erectile Function. Aging, diabetes, psychiatric illness, and prescription drugs collectively are implicated in the sexual dysfunction of millions of men and women in the United States. In addition to potential peripheral effects on the genitalia, all of these conditions impact the neuroendocrine axis. The central nervous system (CNS) plays a critical role in the initiation of penile and vaginal engorgement, and controls the interplay of physiological, psychological, and social processes involved in the human sexual response. Sexual behavior and an active sex life play an important role in promoting a sense of well-being and quality of life, issues that persist into old age. Melanocortin neuropeptides such as alpha-melanoeyte stimulating hormone (MSH) induce penile erection via an action in the hypothalamus. The receptor subtype responsible for erection is unknown. MT-n, a non-specific melanocortin (MC) agonist, initiates erection and increases sexual desire in men with El); we have novel preliminary data suggesting that MT-II acts in the spinal cord as well as the brain. Our overall hypothesis is that melanocortins are required for physiologically significant sex behaviors and represent an important therapeutic approach to sexual dysfunction. This proposal is designed, using a rat model, to 1) identify the specific melanocortin receptor(s) in the brain and spinal cord responsible for penile erection and 2) determine whether endogenous activation of melanocortinergic neurons occurs during normal erectile activity. Specific Aim 1 will use pharmacological methods and unique melanocortin peptide ligands to test the hypothesis that MC4 receptors in the brain and spinal cord mediate penile erection. Specific Aim 2 will determine whether copulatory behavior and non-contact erections activate hypothalamic and spinal POMC neurons, and cause these neurons to release a-MSH. A more detailed understanding of the role of neural melanocortin signaling in penile erection will advance the field of the neuroendocrinology of male sex behavior. The findings may allow us to develop receptor-specific therapeutic strategies, which may ultimately be beneficial to men and women with sexual dysfunction.